This invention relates to novel compounds having an antiviral activity, in detail indole derivatives having an inhibitory activity against viral integrase, and pharmaceutical compositions containing them, especially anti-HIV drugs.
Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The drug for treatment of AIDS is mainly selected from the group of reverse transcriptase inhibitors (AZT, 3TC, and the like) and protease inhibitors (Indinavir and the like), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant virus. Thus, the development of anti-HIV drugs having the other mechanism of action has been desired.
In the above circumstance, integrase has recently been thought to be noteworthy, which is an enzyme relating to the site-specific insertion of viral DNA into chromosome in animal cells, and the research for anti-HIV drugs based on said enzyme inhibition activity is performed ((1) Proc. Natl. Acad. Sci. USA 61 (3), 1013-1020 (1968), KOURILSKY P et al.; (2) J. VIROL. METHODS (NETHERLANDS), 17/1-2(55-61) (1987), F Barin et al.; (3) Proc. Natl. Acad. Sci. USA 90: 2399 (1993), Fesen. M R (1993); (4) CDC AIDS Weekly Pagination:P2 (1990), DeNoon, D J). Some integrase inhibitors has recently been reported, for example, peptide derivatives described in U.S. Pat. No. 5,578,573, tetrahydronaphthyl derivatives described in GB 2306476A, and acrydone derivatives described in WO 97/38999.
Additionally, in the literature, Khim. Geterotsikl. Soedin. 1973, (11), 1519, some kind of indole derivatives are described, but their therapeutic activity is not described. Moreover, in U.S. Pat. No. 5,475,109, non-condensed heterocyclic compounds substituted with dioxobutanoic acid are described to be useful as an anti influenza viral drug, whose mechanism of the action is the inhibition of cap-dependent endonuclease.
In the circumstance above, the development of a novel integrase inhibitor is desired. The present inventors have studied intensively to find out that novel indole derivatives have an inhibitory action on integrase, and are useful as antiviral drugs, especially anti-HIV drugs, to accomplish the present invention shown below.
(1) A compound of the formula: 
wherein
R1 is hydrogen, lower alkyl, cycloalkyl lower alkyl, lower alkylsulfonyl, lower alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylsulfonyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heteroarylsulfonyl, lower alkoxycarbonyl, optionally substituted sulfamoyl, or optionally substituted carbamoyl;
R2 is hydrogen, lower alkyl, lower alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted arylcarbonyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted arylthio, optionally substituted arylsulfinyl, optionally substituted arylsulfonyl, optionally substituted heterocyclyl lower alkyl, or optionally substituted heterocyclyl sulfonyl;
R3, R4, R5, and R6 each is independently hydrogen, halogen, trihalogenated lower alkyl, hydroxy, lower alkoxy, nitro, amino, optionally esterified carboxy, optionally substituted aralkyloxy, or optionally substituted arylsulfonyloxy;
X is hydroxy or optionally substituted amino;
Y is COOR (R is hydrogen or an ester residue), optionally substituted aryl, or optionally substituted heteroaryl,
provided that a compound wherein R1, R2, R3, R5, and R6 each is hydrogen; R4 is hydrogen, methoxy, or chloro; X is hydroxy; and Y is COOC2H5 is excluded, (hereinafter referred to as a compound (I)), a tautomer, or a pharmaceutically acceptable salt, or a hydrate thereof.
(2) The compound according to above (1) wherein R1 and R2 are not hydrogens at the same time when Y is COOR (R is as defined above).
(3) The compound according to above (1) wherein R1 and R2 are not hydrogens at the same time when X is hydroxy and Y is COOR (R is as defined above).
(4) The compound according to any one of above (1)-(3) wherein R1 is hydrogen or optionally substituted arylsulfonyl.
(5) The compound according to any one of above (1)-(3) wherein R2 is hydrogen, optionally substituted aryl, or optionally substituted aralkyl.
(6) The compound according to any one of above (1)-(3) wherein R3, R4, R5, and R6 each is independent hydrogen or halogen.
(7) The compound according to above (6) wherein R3, R5, and R6 are all hydrogens.
(8) The compound according to any one of above (1)-(3) wherein X is hydroxy.
(9) The compound according to above (1) wherein Y is optionally substituted heteroaryl.
(10) The compound according to above (9) wherein said heteroaryl is a 5- or 6-membered ring containing at least one nitrogen atom.
(11) The compound according to above (10) wherein said heteroaryl is tetrazolyl, triazolyl, or imidazolyl.
(12) The compound according to any one of above (1)-(3) wherein R1 is hydrogen or optionally substituted arylsulfonyl; R2 is hydrogen, optionally substituted aryl, or optionally substituted aralkyl; R3, R4, R5, and R6 each is independently hydrogen or halogen; X is hydroxy.
(13) The compound according to above (1) wherein R1 is hydrogen or optionally substituted arylsulfonyl; R2 is hydrogen, optionally substituted aryl, or optionally substituted aralkyl; R3, R4, R5, and R6 each is independently hydrogen or halogen; X is hydroxy; Y is optionally substituted heteroaryl.
(14) The compound according to above (13) wherein R1 is hydrogen or phenylsulfonyl optionally substituted with halogen; R2 is hydrogen, phenyl optionally substituted with halogen, or phenylmethyl optionally substituted with halogen; R4 is halogen; R3, R5, and R6 are all hydrogens at the same time; X is hydroxy; Y is tetrazolyl.
(15) A pharmaceutical composition containing, as an active ingredient, an indole derivative having a group of the formula: xe2x80x94C(O)CHxe2x95x90C(X)Y (wherein X and Y are as defined above) at the 3-position.
(16) A pharmaceutical composition containing the compound according to any one of above (1)-(14) as an active ingredient.
(17) A composition for inhibiting integrase which contains the compound according to any one of above (1)-(14).
(18) An antiviral composition which contains the compound according to any one of above (1)-(14).
(19) An anti-HIV composition which contains the compound according to any one of above (1)-(14).
(20) An anti-HIV medical mixture comprising a reverse transcriptase inhibitor and/or a protease inhibitor in addition to the integrase inhibitor according to above (17).
The compound (I) of the present invention is characterized in that the indole ring has a group of the formula: xe2x80x94C(O)CHxe2x95x90C(X)Y at the 3-position.
The terms used in the specification are explained below. Each term by itself or as part of (an)other substituent(s) means the same unless particularly mentioned.
The term xe2x80x9clower alkylxe2x80x9d is, for example, a C1-C6 straight or branched chain alkyl group, which includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, and the like. A preferable embodiment is C1-C4 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
The term xe2x80x9clower alkoxyxe2x80x9d is, for example, a C1-C6 straight or branched chain alkoxy group, which includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, and the like. A preferable embodiment is C1-C4 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
The term xe2x80x9ccycloalkyl lower alkylxe2x80x9d is, for example, the above-mentioned lower alkyl group substituted with C3-C6 cycloalkyl, which includes cyclopropyl methyl, 2-cyclopropyl ethyl, 4-cyclopropyl butyl, cyclopentyl methyl, 3-cyclopentyl propyl, cyclohexyl methyl, 2-cyclohexyl ethyl, and the like. A preferable embodiment is C1-C4 alkyl substituted with cyclopropyl, for example, cyclopropyl methyl, 2-cyclopropyl ethyl, and 4-cyclopropyl butyl.
The term xe2x80x9clower alkylsulfonylxe2x80x9d is, for example, a sulfonyl group substituted with the above-mentioned lower alkyl, which includes methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl, and the like. A preferable embodiment is sulfonyl substituted with C1-C4 alkyl, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl.
The term xe2x80x9clower alkylcarbonylxe2x80x9d is, for example, a carbonyl group substituted with the above-mentioned lower alkyl, which includes, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, and the like. A preferable embodiment is carbonyl substituted with C1-C4 alkyl, for example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl.
The term xe2x80x9clower alkoxycarbonylxe2x80x9d is an carbonyl group substituted with the above-mentioned lower alkoxy, which includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, n-hexyloxycarbonyl, isohexyloxycarbonyl, and the like. A preferable embodiment is carbonyl substituted with C1-C4 alkoxy, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl.
The term xe2x80x9carylxe2x80x9d is, for example, phenyl, naphthyl, or polycyclic aromatic hydrocarbone (phenanthry, and the like), and the like. A preferable embodiment is phenyl and naphthyl.
The term xe2x80x9caralkylxe2x80x9d is, for example, the above-mentioned lower alkyl group substituted with the above-mentioned aryl, which includes benzyl, 2-phenethyl, 1-naphthylmethyl, 2-(2-naphthyl)ethyl, and the like. A preferable embodiment is benzyl.
The term xe2x80x9caralkyloxyxe2x80x9d is, for example, an oxy group substituted with the above-mentioned aralkyl, which includes benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy, 2-(2-naphthyl)ethyloxy, and the like.
The term xe2x80x9carylcarbonylxe2x80x9d is, for example, a carbonyl group substituted with the above-mentioned aryl, which includes benzoyl, naphthylcarbonyl, and the like.
The term xe2x80x9carylthioxe2x80x9d is, for example, a thio group substituted with the above-mentioned aryl, which includes phenylthio, naphthylthio, and the like.
The term xe2x80x9carylsulfinylxe2x80x9d is, for example, a sulfinyl group substituted with the above-mentioned aryl, which includes phenylsulfinyl, naphthylsulfinyl, and the like.
The term xe2x80x9carylsulfonylxe2x80x9d is, for example, a sulfonyl group substituted with the above-mentioned aryl, which includes phenylsulfonyl, naphthylsulfonyl, and the like.
The term xe2x80x9carylsulfonyloxyxe2x80x9d is, for example, a sulfonyloxy group substituted with the above-mentioned aryl, which includes phenylsulfonyloxy, naphthylsulfonyloxy, and the like.
The term xe2x80x9cheteroarylxe2x80x9d is, for example, a 5- or 6-membered aromatic cyclic group containing 1 to 4 same or different hetero atoms selected from the group of N, O, and S, which includes furyl, thienyl, pyrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazolyl, thiazolyl, and the like. The term xe2x80x9cheteroarylsulfonylxe2x80x9d is, for example, a sulfonyl group substituted with the above heteroaryl, which includes furylsulfonyl, thienylsulfonyl, pyrolylsulfonyl, oxazolylsulfonyl, thiazolylsulfonyl, imidazolylsulfonyl, pyrazolylsulfonyl, thiazolylsulfonyl, pyrolylsulfonyl, pyridazinylsulfonyl, pyrimidinylsulfonyl, pyrazinylsulfonyl, triazinylsulfonyl, tetrazolylsulfonyl, and the like.
The term xe2x80x9cheteroaralkylxe2x80x9d is, for example, the above-mentioned lower alkyl group substituted with the above-mentioned heteroaryl, which includes furylmethyl, thienylmethyl, 2-thienylethyl, pyrolylmethyl, 2-pyrolylethyl, oxazolylmethyl, 3-thiazolylpropyl, 4-imidazolylbutyl, pyrazolylmethyl, 2-triazolylethyl, pyridylmethyl, 2-pyridinylethyl, 3-pyridazinylpropyl, pyrimidinylmethyl, 2-pyrazinylethyl, 3-triazinylpropyl, 4-tetrazolylbutyl, and the like.
The term xe2x80x9cheterocyclylxe2x80x9d is a 5- to 7-membered non-aromatic cyclic group containing 1 to 3 same or different hetero atoms selected from the group or N, O, and S, which includes, for example, morpholinyl, piperadinyl, dioxanyl, piperidinyl, pyrolidinyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, thiazolinyl, oxazolinyl, imidazolinyl, and the like.
The term xe2x80x9cheterocyclyl lower alkylxe2x80x9d is the above-mentioned lower alkyl group substituted with heterocyclic, preferably, morpholinomethyl, and the like.
The above-mentioned xe2x80x9carylxe2x80x9d, xe2x80x9carylcarbonylxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9carylsulfonyloxyxe2x80x9d, xe2x80x9caralkylxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, xe2x80x9cheteroarylxe2x80x9d, xe2x80x9cheteroarylsulfonylxe2x80x9d, xe2x80x9cheteroaralkylxe2x80x9d, xe2x80x9carylthioxe2x80x9d, xe2x80x9carylsulfinylxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9cheterocyclyl lower alkylxe2x80x9d, and xe2x80x9cheterocyclyl sulfonylxe2x80x9d, if substituted, each may be substituted with same or different 1 to 4 substutuent(s) at any substitutable position (ortho, meta, and/or para), which includes, for example, hydroxy, carboxy, halogen (e.g., F, Cl, and Br), trihalogenated lower alkyl (e.g., CF3, CH2CF3), lower alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl), lower alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl), nitro, amino, amino substituted with lower alkyl (e.g., methylamino, ethylamino, dimethylamino), azido, aryl (e.g., phenyl), aralkyl (e.g., benzyl), an amino-protective group (e.g., trityl), and the like.
xe2x80x9cHalogenxe2x80x9d includes F, Cl, Br, and I.
xe2x80x9cTrihalogenated lower alkylxe2x80x9d includes trifluoromethyl, trichloromethyl, tribromomethyl, trifluoroethyl, and the like.
The substituent of xe2x80x9coptionally substituted sulfamoylxe2x80x9d and xe2x80x9coptionally substituted carbamoylxe2x80x9d in R1 includes optionally substituted phenyl and lower alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl).
The substituent of xe2x80x9coptionally substituted aminoxe2x80x9d in X includes lower alkyl (e.g., methyl, ethyl), lower alkoxyalkyl (e.g., ethoxymethyl, ethoxyethyl), aralkyl (e.g., benzyl), and the like.
The ester residue of R in Y, or that of xe2x80x9coptionally esterified carboxyxe2x80x9d in R3, R4, R5, and R6 includes lower alkyl (e.g., methyl, ethyl, tert-butyl), aralkyl (e.g., benzyl, diphenylmethyl), and the like.
Preferable examples of each substituent of the compound (I) are shown below.
A preferable example of R1 includes hydrogen, methyl, n-butyl, cyclopropylmethyl, dimethylsulfamoyl, dimethylcarbamoyl, isopropylsulfonyl, morpholinosulfonyl, tert-butoxycarbonyl, optionally substituted phenylcarbamoyl (the substituent: e.g., halogen), optionally substituted phenylsulfonyl (the substituent: e.g., trifluoromethyl, methyl, isopropyl, benzyl, halogen, methoxy, carboxy, methoxycarbonyl), optionally substituted benzyl (the substituent: azido, halogen, phenyl, carboxy, methoxycarbonyl, nitro, amino), 2-phenethyl, 1-naphthylmethyl, pyridylmethyl, optionally substituted thienyl (the substituent: e.g., carboxy, methoxycarbonyl), and the like. More preferable example includes hydrogen or optionally substituted phenylsulfonyl.
A preferable example of R2 includes hydrogen, n-butyl, optionally substituted phenyl (the substituent: e.g., halogen, methoxy, dimethylamino), optionally substituted benzyl, or phenylpropyl (the substituent: e.g., halogen, methoxy, carboxy, methoxycarbonyl), phenylcarbonyl, optionally substituted phenylthio (the substituent: e.g., halogen, methoxy), optionally substituted phenylsulfinyl (the substituent: e.g., halogen), optionally substituted phenylsulfonyl (the substituent: e.g., halogen, methoxy), morpholinomethyl, and the like. More preferable example includes hydrogen, optionally substituted phenyl, and optionally substituted benzyl.
A preferable embodiment of R3, R4, R5, and R6 is that all are hydrogens or that R4 is halogen (especially, chlorine) and the others are hydrogens.
Preferable example of X is hydroxy.
Preferable example of Y includes COOR (R is hydrogen or an ester residue), or optionally substituted heteroaryl. Preferable example of R is hydrogen in light of the anti viral activity. Moreover the compound wherein R is an ester residue is useful as a synthetic intermediate. Preferable example of heteroaryl in Y is a 5- or 6-membered cyclic group containing at least one nitrogen atom in the ring, more preferably, tetrazolyl, triazolyl, imidazolyl, and thiazolyl, especially, tetrazolyl.
The compound (I) usually shows chemical equilibrium in a solution and the like as shown below. 
wherein R7 is hydrogen or the substituent on the imino group.
In the chemical equilibrium shown above, the compound (Ixe2x80x2, wherein Zxe2x95x90O) is the diketone derivative of the compound (I, wherein Xxe2x95x90OH), and the compound (Ixe2x80x3) and the compound (I) are cis-trans isomers with respect to the olefin part of the 3-side chain. All the theoretically possible tautomers of the compound (I) including these compounds are in the scope of the present invention. In the specification, the term xe2x80x9cthe compound (I)xe2x80x9d may be merely used as general term of the compound (I) and its all tautomers. Moreover, most of N.M.R. data in the following examples correspond to the above-described form (I) depending on the measuring condition.
As a salt of the compound (I), any of pharmaceutically acceptable salts can be used, including base addition salts, for example, alkali metal salts such as sodium or potassium salts; alkaline-earth metal salts such as calcium or magnesium salts; ammonium salts; aliphatic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, or procaine salts; aralkylamine salts such as N,N-dibenzylethylenediamine salts; heterocyclic aromatic amine salts such as pyridine, picoline, quinoline, or isoquinoline salts; quaternary ammonium salts such as tetramethylammonium, tetraethylammonium, benzyltrimethylammonium, benzyltriethylammonium, benzyltributylammonium, methyltrioctylammonium or tetrabutylammonium salts; and basic amino acid salts such as arginine or lysine salts. Acid addition salts include, for example, mineral acid salts such as hydrochlorides, sulfates, nitrate, phosphates, carbonates, hydrogen carbonates or perchlorates; organic acid salts such as acetates, propionates, lactates, maleates, fumarates, tartrates, malates, succinates, or ascorbates; sulfonates such as methanesulfonates, isethionates, benzenesulfonates, or p-toluenesulfonates; and acidic amino acid salts such as aspartates or glutamates.
Furthermore, hydrates and various solvates of the compound (I) are in the scope of the present invention.
The method of the preparation of the compound (I) is explained below.
The compounds (I) are novel indole derivatives, on the other hand, known compounds having indole structure as a basic skeleton have already been reported (Hetrocyclic Compounds, Indoles Part 1-3, (Wiley Interscience), The chemistry of Indoles (Academic Press), etc.). Accordingly, a person skilled in the art can easily prepare the compounds (I), for example, by applying these known compounds as starting materials to widely known organic reactions. The representative general method of the preparation of the compound (I) is shown below.
(1) Forming of the 3-side Chain (The Basic Synthetic Route) 
(A) In case of Xxe2x95x90OH
For example, various 3-acetylindole derivatives (II) obtained in accordance with the methods described in the literature (Tetrahedron 48, 10645(1992)) and the like, react with the above compound (III) (wherein L is a leaving group, for example, a halogen or OR8 (R8 is a lower alkyl and the like) and the like), preferably in the presence of base, to give the compound (Ia).
Examples of the reaction solvent include tetrahydrofuran (THF), dioxane, and the like. Examples of the base include sodium ethoxide, potassium t-butoxide, lithium bis(trimethylsilyl)amide (LHMDS), and the like. The reaction temperature is approximately xe2x88x92100 to 100xc2x0 C., preferably xe2x88x9270 to 60xc2x0 C.
Examples of the compound (III) include dimethyl oxalate, (diethyl oxalate), methyl oxalyl chloride, (ethyl oxalyl chloride), 2-trityl-2H-tetrazole-5-carboxylic acid ethyl ester, 1-trityl-1H-1,2,4-triazole-3-carboxylic acid ethyl ester, 1-tritylimidazole-2-carboxylic acid ethyl ester, phthalic anhydride, o-methoxybenzoly chloride, and the like.
(B) In case of Xxe2x95x90NHR7 
The above compound (Ia) reacts with the above compound (IV) (R7 is a hydrogen or the substituent on the amino group) or their acid addition salt to give the compound (Ib).
Examples of the reaction solvents include methanol, ethanol, and the like. The reaction temperature is approximately xe2x88x9210 to 100xc2x0 C., preferably room temperature to 100xc2x0 C.
(2) The Introduction of the Substituent (R1) at the 1-position 
For example, the above compound (V) obtained in accordance with the method described in (I) can react with the compound (VI) (wherein L is a leaving group), or isocyanate derivatives which can be introduced as R1, or the like, if desired in the presence of base, to give the compound (I).
Examples of the bases include NaH, K2CO3, and the like. Examples of the solvents include THF, dioxane, and the like.
Examples of the compound (VI) include various kinds of sulfonyl chloride (e.g., (substituted) benzenesulfony chloride, 2-thiophenesulfonyl chloride, (substituted) aminosulfonyl chloride, alkylsulfonyl chloride, and the like), halogenated alkyl (e.g., methyl iodide, butyl bromide, cyclopropyl bromide, and the like), halogenated aralkyl (e.g., (substituted) benzyl, picolyl, naphthyl, biphenylmethyl, and the like), carbamoyl chloride (e.g., dimethylcarbamoyl chloride and the like), halogenated acyl (e.g., p-p-fluorobenzoyl chloride and the like), and the like.
Examples of isocyanate derivatives include (substituted) aryl isocyanate (e.g., phenyl isocyanate and the like), and the like.
The reaction temperature is approximately xe2x88x92100 to 100xc2x0 C., preferably xe2x88x9220 to 60xc2x0 C. Moreover, this reaction is suitable for the case of Xxe2x95x90OH.
Before the reaction described in any one of (1) or (2), if desired, the functional group may be protected in accordance with methods widely known to a person skilled in the art, and after that, if desired, ester hydrolysis or deprotection may be carried out.
Use of the compounds of the present invention is explained below.
The compounds (I) are useful as pharmaceutical compositions such as antiviral drugs. The compounds (I) have remarkable inhibition activity against viral integrase. Accordingly, the compounds (I) can be used for the prevention or treatment of various diseases caused by virus which at least produce integrase to grow in infected animal cells. For example, the compounds are useful as integrase inhibitors against retrovirus (e.g., HIV-1 and the like) and as anti-HIV drugs.
Furthermore, the compounds (I) can be used in the combination therapy with anti-HIV drugs having a different mechanism of action such as reverse transcriptase and/or protease inhibitor.
The compounds (I) of the present invention can be administered orally or parenterally. For oral administration, the compounds of the present invention can be used in any form of usual formulations, for example, solid formulations such as tablets, powders, granules, capsules; aqueous formulations; oleaginous suspensions; solutions such as syrup or elixir. For parenteral administration, the compounds of the present invention can be used as an aqueous or oleaginous suspension injection, or nose drops. In the preparation of such formulations, conventional excipients, binding agents, lubricants, aqueous solvents, oleaginous solvents, emulsifying agents, preservatives, stabilizers, and the like can be optionally used.
Although an appropriate dosage of the compound of the present invention varies depending on the administration route, age, body weight, conditions of the patient, and kind of disease, in the case of oral administration, the daily dosage can be between approximately 0.05-3000 mg, preferably approximately 0.1-1000 mg, an adult a day. The daily dosage can be administered in divisions. In the case of parenteral administration, the daily dosage can be between approximately 0.01-1000 mg, preferably approximately 0.05-500 mg.
Furthermore, all kinds of indole derivatives having the group of the formula: xe2x80x94C(O)CHxe2x95x90C(X)Y wherein X and Y are defined above, at the 3-position of the indole can be used as pharmaceutical compositions such as antiviral drugs, as well as the compound (I). In said indole derivative, a wide variety of substituents can be introduced at any position other than the 3-position, as far as they do not have a negative effect on the pharmacological activity. The above indole derivatives can be prepared in accordance with the preparation of the compound (I).
The compound (I) are useful as intermediates of drug, starting materials of the preparation, and the like. For example, the compounds (I) wherein R defined in Y is an ester residue can be easily derived to the compound wherein R is a hydrogen by deprotection.
Examples of the present invention are shown below. Reactions are usually carried out under nitrogen atmosphere, and reaction solvents are used as dried over molecular sieve and the like. Extracts are dried over sodium sulfate or magnesium sulfate and the like.
(Abbreviation)
Me=methyl; Et=ethyl; iPr=isopropyl; Ph=phenyl; Bn=benzyl; Ac=acetyl; Boc=t-butoxycarbonyl; MeOH=methanol; EtOH=ethanol; MEK=methyl ethyl ketone; EtOAc=ethyl acetate; CHCl3=chloroform; MeCN=acetonitrile; DMF=N,N-dimethylformamide; DMA=N,N-dimethylacetamide; Et2O=ethylether; ixe2x80xa2Pr2O=isopropylether; LHMDS=lithium bis(trimethylsilyl)amide; Hex=n-hexane; THF=tetrahydrofuran; DMSO=dimethylsulfoxide; aq.dioxane=aqueous dioxane; Tet=2-H-tetrazol-5-yl; Tri=1H-[1,2,4]-triazol-3-yl; Imi=2-imidazolyl. Furthermore, as an example for expression of the substituents, Ph(2,5-Cl) represents phenyl group substituted with Cl at 2- and 5-position.